Esophageal cancer is the 6th most common cancer in the world and 4th most common in China, respectively, with more than 90% of all cases being the esophageal squamous cell carcinoma (ESCC). The carcinogenesis for ESCC is poorly understood, and there is increasing evidence that Human Papilloma Virus (HPV) may play a major role in the etiology of ESCC. We propose to perform a molecular epidemiological observational study (using case-control designs, with supplemental case-case comparisons) to analyze how HPV-16 infection influences risk to ESCC in a high incidence population in the An'yang area of China. We will conduct a case control study to test HPV-16 as a causal factor for ESCC while adjusting for potential confounders and effect modifiers. We plan to recruit 200 incident cases of ESCC from hospitals in the An'yang area and approximately 200 controls screened by endoscopy from a sample of 400 non- symptomatic subjects from the community. Controls will be frequency matched to the cases for age, gender and residence area. Several methods will be used to measure exposure to HPV in tumor cells from cases and in epithelial cells from controls. Additionally, host genotype (particularly HLA B22 genotypes) will be tested as a risk factor within this case-control design. To delineate and characterize a sub-set of ESCC cases most strongly associated with HPV infection, we will compare HPV+ and HPV- cases for demographic variables and recognized risk factors, as well as a survival analysis within this cohort of cases. We will also consider host genotype (in particular the p53 codon 72 variant). This will be one of the first comprehensive epidemiological studies specifically testing HPV as a causal factor for ESCC in the An'yang area. The proposed molecular epidemiological study may ultimately provide invaluable insight in the etiology of ESCC, the determination of HPV infection as one of the most important causal factors for ESCC in this area will provide new therapeutic targets. [unreadable] [unreadable] [unreadable]